title: In silico prediction of efavirenz and rifampicin drug-drug interaction considering weight and CYP2B6 phenotype.
abstract: OBJECTIVE
  This study aimed to test whether a pharmacokinetic simulation model could extrapolate nonclinical drug data to predict human efavirenz exposure after single and continuous dosing as well as the effects of concomitant rifampicin and further to evaluate the weight-based dosage recommendations used to counteract the rifampicin-efavirenz interaction.
  
  
  METHODS
  Efavirenz pharmacokinetics were simulated using a physiologically based pharmacokinetic model implemented in the Simcyp™ population-based simulator. Physicochemical and metabolism data obtained from the literature were used as input for prediction of pharmacokinetic parameters. The model was used to simulate the effects of rifampicin on efavirenz pharmacokinetics in 400 virtual patients, taking into account bodyweight and CYP2B6 phenotype.
  
  
  RESULTS
  Apart from the absorption phase, the simulation model predicted efavirenz concentration-time profiles reasonably well, with close agreement with clinical data. The simulated effects of rifampicin co-administration on efavirenz treatment showed only a minor decrease of 16% (95% confidence interval 13-19) in efavirenz area under the concentration-time curve, of the same magnitude as what has been clinically observed (22%). Efavirenz exposure depended on CYP2B6 phenotype and bodyweight. Increasing the efavirenz dose during concomitant rifampicin was predicted to be most successful in patients over 50 kg regardless of CYP2B6 status.
  
  
  CONCLUSIONS
  Our findings, although based on a simulation approach using limited in vitro data, support the current recommendations for using a 50 kg bodyweight cut-off for efavirenz dose increment when co-treating with rifampicin.
authors.affiliation: Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. michael.ashton@gu.se
authors.forename: Dinko
authors.initials: D
authors.lastname: Rekić
authors.forename: Daniel
authors.initials: D
authors.lastname: Röshammar
authors.forename: Jackson
authors.initials: J
authors.lastname: Mukonzo
authors.forename: Michael
authors.initials: M
authors.lastname: Ashton
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D003198:Computer Simulation; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005544:Forecasting / Q000379:methods; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008962:Models, Theoretical; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010641:Phenotype; D012293:Rifampin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000904:Antibiotics, Antitubercular; D048588:Benzoxazines; D003521:Cyclopropanes; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz; D012293:Rifampin